Diabetes is a metabolic disorder caused by interaction of genetic, environmental, immunological, as well as life-style factors. The World Health Organization estimates that 366 million people worldwide will suffer from diabetes by year 2030 [Wild S. et al., Diabetes Care 2004, 27, 1047-1053].
According to the American Diabetes Association (ADA; http://www.diabetes.org/home.jsp) four major categories of diabetes have been identified including:                Type 1 diabetes mellitus: The body's fails to produce insulin.        Type 2 diabetes mellitus: Results from insulin resistance, combined with relative insulin deficiency.        Gestational diabetes: Occurs during pregnancy.        Impaired glucose tolerance (i.e. prediabetes): When a person's blood glucose levels are higher than normal but not high enough for a diagnosis of type 2 diabetes.        
Diabetic neuropathy comprises a number of conditions affecting peripheral nerves. It is the most common of the long-term diabetic complications. In fact, diabetic neuropathy is now the most common neuropathy in industrialized countries and may be the most common in the world. The prevalence of sensory neuropathic symptoms, particularly pain, is about 30% among patients with diabetes. Moreover, the prevalence of diabetic neuropathy increases with age, from about 5% in patients between the ages of 20 and 29 to approximately 44% in those between the ages of 70 and 79, and with duration of disease, particularly after 20 years. Prevalence is also higher in patients with poor glycemic control. The most prominent manifestations of diabetic neuropathy are pain and trophic ulcers (e.g., diabetic foot ulcers), both of which are associated with considerable morbidity and disability [Said G. Advanced Studies in Medicine 2001, 1 (11), 457-459].
Peripheral neuropathy can result in a loss of sensation that can lead to neuropathic ulcers, and this is a leading cause of amputation [Poncelet A. N., Geriatrics. 2003, 58(6), 16-8, 24-5, 30; Vileikyte L. Diabetes Metab. Res. Rev. 2004, 20 Suppl 1, S13-18].
Diabetic peripheral neuropathy (DPN, also called distal symmetric neuropathy or sensorimotor neuropathy or diabetic polyneuropathy) is one of the most common complications of both type 1 and type 2 diabetes. In a population-based study [Abbott C. A. et al., Diabet. Med. 2002, 19: 377-384], 22% of the diabetic cohort had peripheral neuropathy that was graded as either moderate or severe. Long-standing peripheral neuropathic pain associated with peripheral neuropathy occurs in one of six diabetic subjects [Daousi C. et al., Diabet. Med. 2004, 21, 976-982].
Most preclinical studies evaluating treatment options for DPN have been carried out in streptozotocin-induced diabetic rodents, which resemble type-1 diabetes. However there is evidence that the etiology and pathology of diabetic neuropathy in type-1 and type-2 diabetes may be different [Sima A. A., Front. Biosci. 2008, 13, 4809-4816].
Research using type-2 diabetic animal models has also been carried out, but less frequently than type-1 [Sima A. A. et al., Diabetologia 2000, 43, 786-793; Li F. et al., Neurobiol. Dis. 2006, 22, 669-676; Oltman C. L. et al., Am. J. Physiol. Endocrinol. Metabol. 2005, 289, E113-E122].
Zucker diabetic fatty (ZDF) rat was first described by Shaw et al. [Proc. Soc. Exp. Biol. Med. 1983, 173(1), 68-75] and Friedman et al. [Am. J. Physiol. 1991, 261(6 Pt 1), E782-E788]. Male obese ZDF (fa/fa or ZDF7Drt-fa; Charles River) are homozygous for a missense mutation causing a nonfunctional leptin receptor (fa/fa). ZDF rats develop obesity, initial hyperinsulinemia (insulin resistance) and then overt diabetes at 8-10 weeks of age [Cheng D. et al., Diabetes Obes. Metab. 2005, 7, 307-317]. Several papers have described neurological abnormalities, including slowed conduction velocity and alterations in sensory testing [Li F. et al., Neurobiol. Dis. 2006, 22, 669-676; Oltman C. L. et al., Diabetes Obes. Metab. 2008, 10, 64-74 among others].
In the pathological course of type-2 diabetes often further complications may arise such as peripheral vascular disease, diabetic neuropathy, diabetic foot problems, diabetic retinopathy and nephropathy. At least some of these complications may cause light, moderate or severe pain symptoms which represent a big problem for the many patients suffering from this disease.
About one-half of patients suffering from type-2 diabetes evidence peripheral polyneuropathy (DPN). This chronic disease is not benign and patients with type-2 diabetes suffer from numerous microvascular and macrovascular complications which cause morbidity and mortality.
The consequences of sensory neuropathy include altered perception of thermal, tactile and vibratory stimuli, involving pain-related symptoms that range from hyperalgesia and allodynia to hypoalgesia [Vinik A. et al., Nature Clinical Practice Endocrinology & Metabolism, 2006, 2, 2-13].
In summary, DPN represents a diffuse symmetric and length-dependent injury to peripheral nerves that has major implications for quality of life (QOL), morbidity, and cost from a public health perspective [Boulton A. J. et al., Diabetes Care 2005, 28, 956-962; Gordois A. et al., Diabetes Care 2003, 26, 1790-1795]. DPN affects 16% of patients with diabetes; it is frequently unreported (12.5%) and more frequently untreated or inadequately treated (39%) [Daousi C. et al., Diabet. Med. 2004, 21, 976-982]. DPN presents an ongoing management problem for patients, caregivers, and physicians. Therefore, there is a need to find new ways for the treatment of type-2 diabetes-associated pain.